TXNIP: An emerging player in ferroptosis arena.

Abstract

Regulated cell death pathways including apoptosis, pyroptosis, and ferroptosis are fundamental to development, tissue homeostasis, and disease progression. Among these, ferroptosis is mechanistically distinct, driven by iron-dependent lipid peroxidation and governed by cellular redox capacity and iron bioavailability. Although glutathione peroxidase-4 (GPX4), using glutathione (GSH), represents the canonical ferroptotic checkpoint, accumulating evidence indicates that ferroptotic susceptibility is also shaped by upstream metabolic and redox determinants. Thioredoxin-interacting protein (TXNIP) has emerged as a potential regulator linking redox imbalance, metabolic reprogramming, and iron mobilization to ferroptotic sensitivity. In this review, we discuss three major mechanisms through which TXNIP modulates ferroptosis: (i) thioredoxin (Trx)-dependent inhibition of antioxidant defenses and promotion of oxidative stress; (ii) Trx-independent metabolic regulation, including glucose transporter type 1 (GLUT1)-mediated NADPH depletion and disruption of GSH and cysteine homeostasis; and (iii) ferritinophagy-mediated iron mobilization and expansion of the labile iron pool. We propose that TXNIP functions primarily as a rheostat of ferroptotic vulnerability upstream of GPX4, modulating the threshold for lipid peroxide accumulation rather than directly executing ferroptotic cell death. We further discuss the role of TXNIP-mediated ferroptotic regulation in disease pathogenesis.